The interrelationship between diabetes mellitus and peripheral arterial disease
A systematic review
Abstract
Summary: This systematic review examined the interrelationship between concomitant diabetes mellitus (DM) and peripheral arterial disease (PAD). The objective was to determine differences in the prevalence as well as in the outcomes in diabetic vs. non-diabetic PAD patients. The current review followed a study protocol that was published online in German in 2017. The search included societal practice guidelines, consensus statements, systematic reviews, meta-analyses, and observational studies published from 2007 to 2020 reporting symptomatic PAD and concomitant DM in patients undergoing invasive open-surgical and endovascular revascularizations. German and English literature has been considered. Eligibility criteria were verified by three independent reviewers. Disagreement was resolved by discussion involving a fourth reviewer. 580 articles were identified. After exclusion of non-eligible studies, 61 papers from 30 countries remained, respectively 850,072 patients. The included studies showed that PAD prevalence differed between diabetic vs. non-diabetic populations (20–50% vs. 10–26%), and further by age, gender, ethnicity, duration of existing diabetes, and geographic region. The included studies revealed worse outcomes regarding perioperative complications, amputation rate, and mortality rate in diabetic patients when compared to non-diabetic patients. In both groups, the amputation rates decreased during the research period. This review emphasizes an interrelationship between PAD and DM. To improve the outcomes, early detection of PAD in diabetic patients, and vice versa, should be recommended. The results of this systematic review may help to update societal practice guidelines.
Introduction
Incidence of diabetes mellitus (DM) as well as prevalence of peripheral arterial disease (PAD) increased over the last decades [1]. One estimate assumes a further increase of DM to 600 million worldwide by 2035 [2, 3]. According to the European Society for Cardiology guideline 2019, one-third of hospitalized patients with PAD suffered from DM [4]. The prevalence of PAD in general populations has been estimated at 10–26%, whereas in DM patients the estimate was 20–28% [2, 5, 6]. In diabetic patients with foot ulceration, the prevalence can exceed 50% [2, 4, 5, 6, 7, 8]. Up to 74% of patients with lower limb amputations have been diagnosed with DM [9].
Regarding the interrelationship of PAD and DM, there was a noticeable change in societal practice guidelines during recent years. Those guidelines began to take notice of the fact that the concomitant incidence of DM and PAD constitutes a special risk that should be specifically considered. The latest guidelines recommended for patients with DM to have a PAD check-up annually as part of a disease management program including a routine measurement of the ankle-brachial-index (ABI) and toe pressure [8, 10, 11, 12]. However, more specific recommendations demanding stricter measures remain sparse. Most studies examined DM or PAD separately, while only few examined their interrelationship comprehensively. In terms of PAD-specific research, DM has been considered rather as a risk factor than as an independent domain [4, 6, 7].
This review examines the specific burden of these two disease groups under the following aspects: prevalence of DM among PAD patients; outcomes (peri- and postoperative morbidity, treatment patterns, amputation rates, mortality) in diabetic vs. non-diabetic patients. The hypothesis is that the interrelationship between DM and PAD may lead to worse outcomes for DM patients.
Methods
The German study protocol was developed and published online in June 2017 (www.idomeneo.de) [13]. The reporting of this systematic review conforms to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement [14]. It covers eligible literature published between 1st January 2007 and 9th August 2020 on the association of PAD and DM. This review was conducted between 1st January 2016 and 9th August 2020.
Criteria for considering studies
Types of studies
Systematic reviews, meta-analyses, observational studies, consensus statements, societal practice guidelines concerning DM in PAD patients were reviewed. PAD was defined as ankle-brachial-index (ABI) <0.9 or >1.3, occurrence of ischaemic intermittent claudication (IC) leading to a reduced walking distance, ischaemic rest pain, or ischaemic wound healing disorders (ulcer, gangrene). PAD and DM prevalence of epidemiological studies and postoperative clinical trial results were processed using Microsoft Excel (Redmond, United States).
The following criteria were used for exclusion: DM associated only with asymptomatic PAD or normal ABI; studies including only patients with primarily cardiac diseases, renal failure, dialysis; carotid/aortic lesions and their invasive treatment; stem cell or cellular therapy/genetic therapy; medical/oxygen therapy; electrical stimulation, radiological/applied procedures.
In addition, a literature search of studies on PAD prevalence in limbs with concomitant DM, and on the outcome of surgically treated PAD with concomitant DM was performed.
Types of participants: male/female patients of any age with DM and PAD.
Types of intervention: any peripheral arterial procedure of the lower limbs, namely percutaneous transluminal angioplasty (PTA), open surgical endarterectomy (EA), hybrid procedures, bypass surgery, or lower limb amputation.
Types of outcome measures: mortality, morbidity, lower limb amputation rates, and revascularization (interventional angioplasty, bypass surgery or surgical procedures to improve blood circulation).
Search strategy
An electronic search was performed using the search engine PubMed (US National Library of Medicine) to access databases from MEDLINE, OLDMEDLINE, and PubMed Central. Additionally, databases of professional societies and organizations were searched for publications that fulfilled the inclusion criteria for types of participants and types of interventions and were available in German or English. The search was run in January 2019 and August 2020. Hence, all publications included were published before 9th August 2020, in either English or German. A detailed search strategy using a combination of the following three terms with corresponding synonyms and MeSH (Medical Subject Headings) terms was used: prevalence, diabetes, peripheral arterial occlusive disease, diabetes and peripheral arterial occlusive disease, therapy, outcome. (See electronic supplementary material [ESM] 1).
Study selection
Identified publications were screened independently by three reviewers (NM, KS, MK) for possible inclusion; full texts of relevant records were independently evaluated for eligibility. A disagreement was resolved by discussion. A fourth reviewer (CAB) confirmed the inclusion of the selected studies and acted as adjudicator in case of substantial disagreement. Included studies and other sources were described by author’s name, title and year of publication, language, and country.
Data extraction
Suitable studies were described by author(s), journal, type of study, patient group, study participants, method, duration of study, time of follow-up and outcome (mortality, morbidity, amputation rates and interventional or surgical revascularization).
Results
The PubMed search identified 580 articles. 102 additional studies were found through a grey literature search. After removal of duplicates, the remaining 476 articles were screened. Of these, 322 missed the eligibility criteria leaving 154 articles for selection. After further exclusion of unsuitable articles, 61 studies remained (Figure 1).
These 61 studies analysed data from a total of 850,072 patients. The data stem from 30 countries and all continents.
Prevalence of PAD and DM
The included studies show that PAD prevalence in DM patients differed depending on age, gender, race, duration of existing diabetes, and geographic region. The mean prevalence of PAD was 10–26% in the general population and 20–28% in diabetic patients [2, 5, 6]. In those with diabetic foot-ulceration, PAD prevalence increased to more than 50% [2, 4, 5, 6, 7]. Few studies reported lower PAD prevalence: without diabetic foot-ulceration (4–8%) [15, 16, 17], and with diabetic foot (33–38%) [18, 19, 20]. There was evidence that the prevalence of this comorbidity increased with the progress of DM. The surveyed studies did not report significant differences between DM type 1 and type 2 patients.
Differences in prevalence by age and gender
Several studies reported that prevalence increased with higher age [20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 48, 49]. In a multinational study from five Asian countries, the prevalence rose from 2% (40–59 years) through 8% (60–74 years) to 18% (>75 years) [22], whereas a Spanish study found a prevalence of 29% (>50 years) [24].
Few studies addressed differences between men and women. They found higher DM prevalence in men [15, 22, 25, 26, 27, 33]. A population-based analysis in 23,715 patients revealed a 10% prevalence of DM in women undergoing percutaneous endovascular revascularizations and a 15% prevalence in men [33]. Adding the non-valid ABI values in males, this study supposed that male patients more often suffer from atherosclerotic diseases below the knee while females primarily suffer from lesions above the knee [33].
Differences in prevalence by geography and ethnicity
Several studies demonstrated regional differences [24, 25, 26, 27, 31, 33]. An Indian study showed age- and gender-dependent prevalence: <40 years (2% men vs. 5% women), 40–60 years (4% vs. 10%), >60 years (11% vs. 20%) [24]. Studies from Central Africa also showed increased PAD prevalence in women [25, 26, 27]. By contrast, a Malaysian study discovered no significant gender differences [29].
Some studies found that also ethnicity and race, and partly the geographic region influence the prevalence of the two concomitant diseases. Two studies from Malaysia and Singapore report a prevalence of PAD with diabetes among the Indian population in Malaysia of 20% [29] and 18% in Singapore [30], while it was 6% among the Malaysian population in Malaysia [29] but 23% among the Malaysian population in Singapore [30]. Among the Chinese population, the prevalence was 19% in Malaysia against 13% in Singapore [30]. In a systematic review from the United States, the prevalence among the white population was 17%, among Afro-Americans 25%, among East-Asians 14%, and among South-Asians only 8% [28]. A study comprising six community-based cohorts from the United States (22% diabetics) reported a lifetime PAD risk of 30% for Afro-Americans, 19% for Whites and 22% for Hispanics. 9% of Afro-Americans were estimated to develop PAD by 60 years of age, while Whites and Hispanics were estimated to reach that percentage at 70 years [32].
Revascularization practice in diabetic vs. non-diabetic populations
Concerning the revascularization rate for the treatment of PAD in diabetics the included studies reported on the outcome of bypass surgery and PTA. Six of them investigated the outcome after revascularization of critical limb ischaemia [34, 35, 36, 37, 38, 39].
The bypass rate ranged from 13% to 27%, whereas PTA was used for 31% to 86% of the patient collectives [1, 28, 34, 35, 36, 37, 38, 39]. In a systematic review, the one-year-survival rate was 85% after bypass surgery and 78% after endovascular intervention. Specifically, for diabetic foot ulcers, 60% healed after one year regardless of the technique used [40]. A study from the United States found no significant differences between diabetics vs. non-diabetics after bypass surgery [39]. Another long-term study on diabetic vs. non-diabetic patients with atherectomy of lower limb arteries showed similar outcomes for both approaches [41]. However, in a meta-analysis, due to postoperative morbidity and mortality, patients with DM had worse outcomes than non-diabetics after PTA and bypass surgery [42]. Lin et al. showed that endovascular first treatment was associated with improved amputation-free survival in diabetic PAD-patients with critical limb ischaemia [43].
Complication rate in diabetic vs. non-diabetic patients
Few studies dealt with perioperative complications after revascularization. For patients with critical limb ischaemia with diabetic foot syndrome, a 32% complication rate after endovascular revascularization and 1% after open surgical intervention was reported [37, 40]. The Eurodiale study found a 69% cure-rate for diabetic foot ulcers when a concomitant PAD and DM was apparent [44]. In a Swedish study (patients with diabetic foot syndrome and PAD; Fontaine stage 4 and Wagner grade 4 to 5), 38% exhibited a primary cure [45, 46].
Amputation rate in diabetic vs. non-diabetic patients
All studies comparing the amputation rate of diabetics with non-diabetics found a significantly higher rate for diabetics [41, 45, 47, 50, 51, 52, 53, 54, 55].
In a 5-year follow-up-study, DM was associated with an increased major amputation rate (hazard ratio (HR) 1.45, 95%, confidence interval (CI) 1.09–1.33) [53]. For the combined endpoint of amputation or death, increased rates were found for DM (HR 1.31, 95% CI 1.23–1.38) [53]. The relative risk of amputation for patients with critical limb ischaemia was 45% [53]. Amputation rates did not differ between PTA and open surgery [53].
A large German study (15,332 patients, Rutherford grade 5 and 6) showed higher 1-year amputation rates for diabetics than for non-diabetics (Rutherford grade 5: 13% vs. 7%, Rutherford grade 6: 48% vs. 37%) [35]. After 4 years, the respective rates increased for diabetics and non-diabetics (Rutherford grade 5: 41% vs. 29%, Rutherford grade 6: 71% vs. 61%) [35].
In a Californian study (40% of the patients <65 years) the amputation rate for men with PAD and DM was 1.5-times higher than for men with PAD alone and 5-times higher than for diabetics without PAD. For women, the amputation rate was 2.5-times higher for PAD and DM than for diabetics without PAD [53, 54]. Among the patients with diabetic foot syndrome, 24% had DM and concomitant PAD [53, 54]. The amputation rate in this group increased from 10% in 2005 to 28% in 2013. Patients with concomitant PAD and DM were 8 years older than patients suffering only from PAD [53, 54]. In another study, 23 out of 1000 patients with DM and PAD underwent a major amputation after surgery or PTA [55]. Depending on age and gender, the amputation rate in France was 12-times higher among diabetics than among non-diabetics [56].
According to a Danish study, the incidence of major amputation was 279 per 100,000 patient years. The risk of amputation increased in female patients later during the follow-up than in male patients. The amputation rate within a follow-up of 19 years was 25% [57]. Another Danish analysis showed that diabetes mellitus (Odds Ratio, OR 1.28, CI 1.17–1.40) was associated with a higher risk of amputation without prior revascularisation. The incidence of major amputations decreased, while revascularisation rates increased. Only 24%–31% of patients having major amputations were treated by a vascular surgeon before amputation and only 25% of them had a revascularisation within the year prior to amputation. Reasons for this could be unawareness of early PAD symptoms, lack of knowledge about vascular reconstruction opportunities, too late presentation of symptoms and underutilisation of revascularisation [58].
For several countries, a significant decrease of major amputation rates was reported: for Germany (2006–2012 by 5%, resp. 2005–2010 by 4%) [59, 60], USA and England (2003–2013 by 17%) [51, 53]. The highest reduction concerned patients over 80 years [61].
Mortality in diabetic vs. non-diabetic patients
Most studies showed higher mortality rates after PAD treatment in diabetics when compared with non-diabetics. The examined time spans ranged from 30 days to 10 years. The longer the time span, the higher were the reported mortality rates [16, 17, 35, 39, 42, 44, 47, 52, 62, 63, 64, 65].
One year after surgical intervention, the mortality rate among diabetics was 10% against 6% in non-diabetics [39]. Another 5-years follow-up study found a mortality rate of 23% for diabetic PAD patients <75 years against 10% for PAD patients and 52% vs. 38% for patients >75 [62]. In the LIPAD study the 5-year mortality rate for PAD patients <75 years was 23% in diabetics vs. 10% in non-diabetics. It increased to 52% for diabetics >75 years [63]. The corresponding 10-year mortality rate was 58% vs. 29% [64].
In a Swedish 5-year follow-up study the mortality rate for diabetics was 2% for patients treated for intermittent claudication and 14% for patients treated for critical limb ischaemia after 6 months, and 12% vs. 41% after 36 months, respectively [45].
An American study on the mortality rate after endovascular revascularization and surgical bypass reported mortality rates of 2% after 30 days and 58% after 10 years in patients with concomitant DM and PAD [37]. In patients with critical limb ischaemia, the mortality rate of diabetics and non-diabetics was the same after 30 days [37].
Another study revealed increased 10-year all-cause mortality in PAD patients (HR 1.35, 95% CI 1.15–1.60), and major macrovascular events (HR 1.47, 95% CI 1.23–1.75) [16]. Increased death rates were found for diabetics when compared to non-diabetics (HR 1.31, 95% CI 1.23–1.38) [52]. There was a slight difference in mortality whereby patients revascularized by open surgery had a slightly higher mortality rate [52].
Lin et al. included 6,000 bypasses and 11,000 endovascular interventions comprising 65% and 58% diabetics, respectively. An endovascular first strategy was associated with improved amputation-free survival in patients with critical limb ischaemia (HR 1.16, 95% CI 1.13–1.20) with no difference in mortality (HR 0.94, 95% CI 0.89–1.11) [43]. Interestingly, endovascular first strategy caused higher rates of reintervention (HR 1.19, 95% CI 1.14–1.23) [43].
By contrast an Italian study found identical mortality rates after 1, 2 and 5 years for diabetics and non-diabetics [66].
Discussion
The current systematic review analysed 61 studies comprising data from 850,072 individuals treated in 30 countries from all continents to illuminate the interrelationship between PAD and concomitant DM (see Table in Electronic Supplementary Material 1). The studies clarified that with DM progression the prevalence of an associated PAD increased. These studies also showed a strong confounding influence of age and gender [20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 33, 49] and a not yet fully examined influence of ethnicity and geography [24, 25, 26, 27, 30, 31, 32, 33, 48, 67, 68, 69, 70]. Concerning morbidity, amputation rate and mortality, worse outcomes in diabetic vs. non-diabetic patients were identified by most included studies. Here again, a modifying impact of age and gender was observed.
The current review confirmed a clear association between concomitant PAD and DM. Their prevalence increased with higher age [20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31] and the duration and progress of DM [9, 16, 24]. There is considerable evidence that the gender aspect matters both for prevalence and outcomes. Whereas most studies on the gender aspect found differences between men and women with respect to PAD and DM, few [29] did not confirm such differences. Those conflicting results may be explained by other, e.g., regional influences. However, the number of studies addressing the complex interaction between the several risk factors and confounders is still limited. Further research on this aspect, especially on the gender aspect, is desirable.
Almost all studies showed a worse outcome for diabetics vs. non-diabetics after open surgery and endovascular treatment of PAD with more perioperative complications, amputations, and higher mortality rates. This may be since diabetic lesions occur over a wider area of the vasculature [41] or by the fact that DM is associated with a more severe disease severity below the knee [41].
In all studies, the amputation rate for concomitant PAD and DM was higher than for PAD alone, although the overall rate decreased even for diabetics [51, 53, 57, 58, 59, 60]. The data from England, Germany, and the United States reflect the success of qualified medical care, which should be improved especially in low income countries.
Also, mortality rates were much higher for DM and PAD patients with a clear association between the severity of PAD in diabetics and corresponding mortality. Critical limb ischaemia was associated with the highest mortality [34, 37]. DM patients had a significantly increased risk of death compared to non-diabetics. This suggests that mortality probability of PAD patients strongly depends on whether the PAD patient suffered from DM.
The data of the current systematic review were partially in contrast to a previous German study where the incidence rates of PAD and concomitant diabetes in longitudinally linked health insurance claims data from inpatients were decreasing in comprehensive trend analyses [6]. A possible explanation could be related to methodological aspects, varying target populations, and the likely impact of preventive medicine.
Furthermore, a Danish case-control study which compared an intensified diabetes therapy with the conventional treatment did not find a significant benefit, after 6 years, in correlation to the de novo incidence of PAD [12]. This is partly contradicted by another more recent Danish study that found that early revascularisation decreased the amputation risk [58].
Also, a 2020 study from a Korean multicenter retrospective registry supports the outcome that screening of diabetic PAD patients at the earliest point of time is indicated. This study investigated the influence of preprocedural glycemic control on clinical outcomes of endovascular therapy in diabetic patients with PAD examining the effect of hemoglobin A1c (HbA1c) on clinical outcomes. Diabetic patients were separated in two groups with a HbA1c level optimal (<7%) or suboptimal (>7%). Although no significant differences were found in both groups in terms of amputation or overall survival, the risk of reintervention was significantly higher in the group of suboptimal glycemic control (log-rank p= 0,048). Suboptimal glycemic control was one of the independent predictors for reintervention [71]. The influence of glucose control on the macrovascular outcomes in DM patients is still controversial. Many studies demonstrated the benefits of intensive glucose control with reducing cardiovascular events and lower extremity amputations and practice guidelines recommend adequate glycemic control [3, 8, 11]. Other studies showed no positive effect of glycemic control [72]. Arya et al. showed that high HbA1c level was associated with a higher risk of amputation [73]. The study included mostly males and approximately 40% were not diagnosed with DM preoperatively [69]. Whether more intensive glycemic control can improve clinical outcomes after endovascular therapy in DM patients with PAD needs further research.
There are limitations that need to be considered. Research published in other languages than German and English was not identified by the current review. Another limitation is that further confounding factors of PAD and their relation to DM have not been comprehensively considered. Also, a possible influence of the DM type (1 vs. 2) was not addressed by the surveyed studies. Further, according to a 2020 study, periodontal treatment has a potential benefit in relation to PAD. The association was independent of gender, age, and concomitant diabetes. Thus, periodontal treatment may be associated with a reduction of hospitalizations due to DM and cardiovascular as well as other diseases and even with significant reductions in medical costs [74]. More influencing factors (such as nicotine, adipositas, DM type) should be thoroughly investigated in further studies. Influential factors may additionally include socioeconomics and income, healthcare expenditures and the availability of limb salvage teams.
Considering all available data, a mutual relationship between DM and PAD could be shown, which influences each other’s impact. DM worsens PAD through the lesions of vessels, and PAD worsens the overall morbidity of DM patients. DM should no longer be considered a mere risk factor for PAD. The two diseases form a concomitant disease group of its own and should be treated as such. A specific treatment strategy for patients with concomitant PAD and DM involving disease management programs and evidence-based revascularization may be beneficial. Detection and treatment of the comorbidity as early as possible is of importance to reduce amputation and mortality. The multidisciplinary cooperation of general practitioners, diabetologists, vascular surgeons, and internal medicine should be intensified so that diabetics with PAD receive the best evidence-based treatment. Furthermore, specific recommendations in societal guidelines should be developed for this distinct group of vulnerable patients.
Conclusions
This systematic review found that PAD prevalence was higher in diabetics when compared to non-diabetics. Patients with concomitant PAD and DM suffered from higher perioperative complication, amputation, and mortality rate. The concomitant existence of DM and PAD and their interrelationship needs greater attention by the community.
Electronic supplementary material
The electronic supplementary material (ESM) is available with the online version of the article at https://doi.org/10.1024/0301-1526/a000925
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